There has been little action to date in the “subsequent entry biologic” (SEB) field in Canada, with few submissions being filed and even fewer biologics patents being challenged.  With the filing of the first SEB patent case, however, things are getting interesting.

As is the case in many other jurisdictions, several patents relating to biologics in Canada have expired this year or will expire later this year or in the following two years.  Notwithstanding these imminent patent expiries, few applications to market SEBs — as biosimilars are known in Canada — are being filed and even fewer applicants are challenging any of the applicable biologics patents.

There may be several reasons for this.  Basic patents may be expiring but, as expected, there are multitudes of other patents that may be problematic — for example, process and formulation patents (aspects which arguably may have increased significance in the area of biologics).  An SEB applicant may “get around” initial patents to obtain a notice of compliance (NOC, i.e., formal approval), only to find itself being sued for patent infringement based on several process patents.  There is procedural uncertainty regarding the U.S. biosimilar pathway introduced in 2010 (the comparatively small Canadian market means that the U.S. market may have a substantive effect on what happens north of the border).  There are fewer players who are capable of, or intent on, testing the waters of the biosimilar space (both from the perspective of Health Canada, who are developing expertise in the “new” area of SEB submissions, and from the perspective of provincial formularies/ market acceptance).  As Health Canada has only released a “general” 2010 SEB guideline, perhaps the introduction of “product-specific” guidelines (as used by the comparatively advanced European regulatory authorities) would assist SEB applicants.

According to data obtained from Health Canada[1], there have been five submissions for SEBs, one of which was approved over three years ago — Sandoz’s somatropin (Omnitrope).  A second SEB is expected to be approved within the next two years —Teva’s filgrastim, an SEB version of Amgen’s Neupogen.  Health Canada has scheduled eight pre-submission meetings (which may or may not relate to the five SEB submissions already received), suggesting that anywhere between 8-13 SEB submissions have been filed or are being considered for filing in Canada.

The Canadian courts have, to date, dealt with very few biologics patents — and indeed no SEB patent cases.  In the past few months, however, there has been an increase in activity in this area, with Amgen filing the first SEB patent case, against Teva[2].

These developments make this an opportune time to report on what is happening on the SEB front in Canada.

Although Canada instituted its guidance on SEBs in March 2010[3], Teva’s filgrastim is the only SEB that is on record as being under review pursuant to this guidance.  By way of comparison, in the EU, where a regulatory framework for biosimilars has been in force since 2005, 19 marketing authorisation applications (MAA) for biosimilars have been reviewed, with 14 positive, four withdrawn and one rejected.  Twelve biosimilar medicinal products current hold a valid MAA and six MAAs are under review[4]

Basic patents may be expiring but, as expected, there are multitudes of other patents that may be problematic

Canadian biologics patents due to expire before the end of 2012 include those relating to Janssen’s monoclonal antibody Remicade (infliximab) and Hoffman’s mAb Avastin (bevacizumab).  Those set to expire in 2013/2014 include those relating to Bayer’s mAb Zevalin (ibritrumomab), Hoffman’s growth hormone Nutropin (somatropin), Amgen’s Eprex (epoetin alfa), GlaxoSmithKline’s Cervarix (HPV), Amgen’s Enbrel (etanercept), Novo Nordisk’s Levemir and Sanofi’s Lantus insulin analogues and Hoffman’s mAb Rituxan (rituximab).

It would be reasonable to assume that the remaining three pending SEB applications also relate to somatropin or filgrastim, or alternatively to epoetin (biosimilars of these three biologics have received approval in the EU).  In addition, Hospira has indicated that it plans to file submissions for infliximab in Canada in the near future (in addition to the U.S., Europe (recently filed) and Australia).

Teva’s Canadian SEB submission became public knowledge in May 2012, when Amgen initiated the first SEB patent case in Canada, revealing thatTeva had filed for approval of filgrastim (as a copy biologic — i.e., SEB — of Neupogen), for stimulating white blood cells in cancer and HIV patients.

According to Canada’s guidance, SEB patent cases follow the same patent linkage “pre-launch” litigation procedures that are used for small molecules (similar to the Hatch Waxman procedures in the U.S.).  The “linked patents” are those specifically set out on the Patent Register.  This is in sharp contrast to the complicated “patent exchange” procedure introduced in the U.S. in March 2010 (according to the Food and Drug Administration, as of spring 2012 no abbreviated biologic applications had been received that would trigger such an exchange)[5].

The U.S. patent exchange procedure involves months of negotiation/ review by brands and biosimilar applicants to simply select possible patents that may be litigated pending biosimilar regulatory review, and other patents that the brand can later try to assert to obtain a last minute injunction six months prior to launch.  Although Teva filed a new drug submission (NDS) for filgrastim in Canada (as opposed to an abbreviated NDS, which is the standard route for generic small molecules), it must still address certain patents that Amgen has listed on the Patent Register.  In addition, there is an eight-year data protection monopoly period for “innovative drugs” that brand name firms can take advantage of. In the case of filgrastim, there were no data protection limitations preventing Teva from filing its NDS.

Amgen v Teva involves only one Amgen patent — CA 1,341,537 (CA’537), which relates to the production of pluripotent granulocyte-colony stimulating factor (G-CSF).  CA’537 was filed in 1986 and took over 20 years to issue.  It is a basic patent and it expires on 31 July 2024.  CA’537 has claims to DNA (expressing G-CSF), processes for making G-CSF, the polypeptide G-CSF (with specific amino acid sequences) and host cells.  Teva has argued that CA’537 is invalid based on double patenting, anticipation, obviousness, conflict with an earlier inventor, utility, invalid selection and bad faith.  Teva brought an impeachment action in the U.S. in 2009 against Amgen, where Teva argued many of the same invalidity grounds.  The U.S. case was ultimately settled by the parties.

In addition to CA’537, there are at least 15 other Amgen patents relating to CSF in Canada.  There are certain timing and subject matter restrictions that limit the number of patents that Amgen can assert against Teva during this period of pre-approval.  Should Teva be successful with respect to CA’537, Amgen certainly has additional patents available to assert against Teva in a standard patent action once Teva obtains its NOC from the Minister of Health and starts selling its filgrastim in Canada.

Teva has been marketing filgrastim in Europe since 2008 (as Tevagrastim) and obtained U.S. market approval for the product this August[6].  The U.S. patent exchange procedure did not apply to Teva’s submission, which was a “standard” new drug submission (biologics licence application) and was made before the FDA introduced its biosimilar pathway in 2010.  Given Canada’s comparatively smaller market size, it is likely that Teva used a foreign reference product for its SEB clinical trials — likely a U.S. or EU product (as is permitted by Health Canada, similar to the February 2012 draft FDA guidelines, but unlike current European regulations — although these are expected to be modified shortly). 

Biologics patent litigation in Canada has tended to be “follow on” litigation from litigation in the U.S.  In addition to the Amgen vs Teva (Neupogen) case, Abbott has brought an infringement case in Canada against Janssen’s Stelera regarding Abbott’s patent for antibodies for psoriasis[7].  Although this is not an SEB case, the fact that biologics patents have rarely been dealt with by Canadian courts means that any validity findings may be useful to future SEB applicants.  The last notable biologics case heard by a Canadian court was in 2000 where Amgen’s recombinant EPO patent was found valid and infringed by Hoffman’s Recormon product.  The parties in the Stelera case recently adjourned a month-long Canadian patent trial pending disposition of Abbott’s U.S. claim for infringement of its equivalent human interleukin antibody patent [8]. Following resolution of summary judgment motions, the U.S. case is being heard over September 2012.

Should companies continue to file biosimilars-type submissions in the U.S. on the basis of an NDS (i.e., without using the FDA’s new biosimilars pathways), we may well see companies starting Canadian NOC cases near to the end of the U.S. approval process (as the Canadian patent linking regime is in place and must be addressed before an NOC is obtained).  This is precisely what Teva appears to have done.  “Public” notice of Teva’s Canadian SEB application was first given in May when the Canadian patent NOC case started.  At the same time, Teva had also applied for approval in the U.S. and, just three months after the Canadian case started, it received approval from the FDA for its filgrastim product.  It is interesting to note that Teva took the standard new drug application route in the U.S. and did not rely on any similarity, but has used the SEB route in Canada and is thereby relying on similarity.  This is probably because Canada has a clearer patent procedure – meaning there are still advantages to using the country’s SEB regulatory approval process.

As companies develop more “global” biosimilar submissions, the existence of Canadian patent litigation may provide early signals that generic companies have sought approval of biosimilars in other countries as well.